In Situ Characterization of Dendritic Cells Occurring in the Islets of Nonobese Diabetic Mice During the Development of Insulitis

Abstract

Type 1 diabetes mellitus in nonobese diabetic (NOD) mice, a well-known model of human type 1 diabetes, has been considered to be caused by the destruction of insulin-producing beta cells in the islets of the pancreas by self-reactive T cells. Antigen-presenting cells like dendritic cells (DCs) and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. These immunohistochemical studies revealed that CD11c-positive DCs already appeared in the islets of NOD mice as early as 4 weeks old when lymphocytes were not yet infiltrated in the islet, and thus insulitis was not developed. DCs were first observed to locate around swollen parainsular vessels. From age 7 weeks onward to age 13 weeks, more DCs were present in parainsular areas where lymphocytes had also accumulated, and the number of DCs in the islets as well as lymphocytes increased. However, at the end stage of insulitis from age approximately 17 weeks onward, the number of DCs in the islets decreased. In contrast, accumulation of DCs in the para- and periislets was not observed in 7- and 17-week-old ICR female mice that do not develop type 1 diabetes. Double-staining studies using confocal laser scanning microscopy showed that the CD11c-positive DCs coexpress both major histocompatibility (MHC) class II and costimulatory molecules, CD80 and CD86. Electron-microscopy studies further demonstrated that cell bodies and processes of the DCs make close contact with lymphocytes. These results suggest that DCs infiltrated into the pancreatic islets are capable of stimulating T cells by the MHC class II-antigenic peptide complex, together with costimulatory molecules, which eventually lead to the beta-cell destruction in NOD mice.

Imaging inflammation of the pancreatic islets in type 1 diabetes

“…Indeed, 3D reconstruction of confocal images of pancreata from BDC2.5 animals perfused with heparinized PBS, then with CMFN probe plus fixative and immediately dissected, suggests a decrease in islet vessel diameter and density as disease unfolds (M.C.D., unpublished data). There have also been reports of changes in macrophages and͞or dendritic cell populations through the evolution of insulitis in NOD mice, in particular in the 3-to 7-wk time window (27)(28)(29).…”

CD4+CD25+ Regulatory T Cells Prevent Type 1 Diabetes Preceded by Dendritic Cell-Dominant Invasive Insulitis by Affecting Chemotaxis and Local Invasiveness of Dendritic Cells

“…Despite these exciting findings, the cellular mechanisms underlying the in vivo protective effect of nTregs against development of insulitis and T1D are still incompletely understood. In addition to T and B cells, innate immune cells, such as DCs, are among the first populations of immune cells detectable in NOD mice islets and may also contribute to insulitis and T1D (10)(11)(12)(13)(14). However, the role of DCs in the development of insulitis and diabetes, and the cellular requirements/mechanisms regulating their migration and infiltration into islets, remain largely unclear.…”

Are mast cells important in diabetes?

“…Macrophages CD11c + and CD11c -and CD4 + Th1 cells play an important role in T1DM since they are infiltrated around the islets of Langerhans in the pancreas, provoking the destruction of insulin-producing β cells in the islets with a consequence of deficiency in insulin production [40]. This phenomenon can be reproduced by transferring the T cell autoimmunity involved from one affected animal to another (healthy animal) [41].…”